RATIONALE: Mice with genetic deletion of the cholesterol efflux transporter, ATP-binding cassette (ABC) G1, have pulmonary lipidosis and chronic pulmonary inflammation. Whether ABCG1 regulates host defense is unknown. OBJECTIVES: To determine whether ABCG1 regulates pulmonary innate immunity and host defense, and to investigate the underlying molecular/cellular mechanisms. METHODS: Abcg1(+/+) and Abcg1(-/-) mice were challenged with intrapulmonary lipopolysaccharide (LPS) or Klebsiella pneumoniae, intravenous K. pneumoniae, or intraperitoneal LPS. Phenotypic responses were profiled. Bone marrow chimeras and in vitro assays were used to differentiate and characterize the role of hematopoietic versus nonhematopoietic ABCG1 in host defense. MEASUREMENTS AND MAIN RESULTS: Unexposed Abcg1(-/-) mice had normal numbers of circulating neutrophils, but increased neutrophil recruitment to the airspace and lung parenchyma, and increased airspace cytokines and chemokines in the steady state. After intrapulmonary LPS or K. pneumoniae, Abcg1(-/-) mice displayed exaggerated further neutrophil recruitment to and degranulation in the airspace, and elevated airspace cytokine/chemokine induction. Alveolar macrophage ABCG1 was critical, as ABCG1 deficiency in hematopoietic cells was sufficient to enhance responses in vivo, and Abcg1(-/-) alveolar macrophages adopted a "foam cell" phenotype, and were hyperresponsive ex vivo. Pulmonary compartmentalization and clearance of K. pneumoniae were increased in Abcg1(-/-) mice, indicating enhanced host defense. By contrast, Abcg1(+/+) and Abcg1(-/-) mice had equivalent responses to intravenous K. pneumoniae and intraperitoneal LPS, suggesting that ABCG1 regulates innate immunity in a tissue-selective manner. CONCLUSIONS: Abcg1(-/-) mice have an enhanced pulmonary host defense response driven predominantly by hematopoietic cells.
RATIONALE: Mice with genetic deletion of the cholesterol efflux transporter, ATP-binding cassette (ABC) G1, have pulmonary lipidosis and chronic pulmonary inflammation. Whether ABCG1 regulates host defense is unknown. OBJECTIVES: To determine whether ABCG1 regulates pulmonary innate immunity and host defense, and to investigate the underlying molecular/cellular mechanisms. METHODS:Abcg1(+/+) and Abcg1(-/-) mice were challenged with intrapulmonary lipopolysaccharide (LPS) or Klebsiella pneumoniae, intravenous K. pneumoniae, or intraperitoneal LPS. Phenotypic responses were profiled. Bone marrow chimeras and in vitro assays were used to differentiate and characterize the role of hematopoietic versus nonhematopoietic ABCG1 in host defense. MEASUREMENTS AND MAIN RESULTS: Unexposed Abcg1(-/-) mice had normal numbers of circulating neutrophils, but increased neutrophil recruitment to the airspace and lung parenchyma, and increased airspace cytokines and chemokines in the steady state. After intrapulmonary LPS or K. pneumoniae, Abcg1(-/-) mice displayed exaggerated further neutrophil recruitment to and degranulation in the airspace, and elevated airspace cytokine/chemokine induction. Alveolar macrophage ABCG1 was critical, as ABCG1 deficiency in hematopoietic cells was sufficient to enhance responses in vivo, and Abcg1(-/-) alveolar macrophages adopted a "foam cell" phenotype, and were hyperresponsive ex vivo. Pulmonary compartmentalization and clearance of K. pneumoniae were increased in Abcg1(-/-) mice, indicating enhanced host defense. By contrast, Abcg1(+/+) and Abcg1(-/-) mice had equivalent responses to intravenous K. pneumoniae and intraperitoneal LPS, suggesting that ABCG1 regulates innate immunity in a tissue-selective manner. CONCLUSIONS:Abcg1(-/-) mice have an enhanced pulmonary host defense response driven predominantly by hematopoietic cells.
Authors: D Rujescu; I Giegling; N Dahmen; A Szegedi; I Anghelescu; A Gietl; M Schäfer; F Müller-Siecheneder; B Bondy; H J Möller Journal: Neuropsychobiology Date: 2000 Impact factor: 2.328
Authors: S J Klebanoff; M A Vadas; J M Harlan; L H Sparks; J R Gamble; J M Agosti; A M Waltersdorph Journal: J Immunol Date: 1986-06-01 Impact factor: 5.422
Authors: Carlos E O Baleeiro; Steven E Wilcoxen; Susan B Morris; Theodore J Standiford; Robert Paine Journal: J Immunol Date: 2003-07-15 Impact factor: 5.422
Authors: Thomas Q de Aguiar Vallim; Elinor Lee; David J Merriott; Christopher N Goulbourne; Joan Cheng; Angela Cheng; Ayelet Gonen; Ryan M Allen; Elisa N D Palladino; David A Ford; Tisha Wang; Ángel Baldán; Elizabeth J Tarling Journal: J Lipid Res Date: 2017-03-06 Impact factor: 5.922
Authors: David W Draper; Kymberly M Gowdy; Jennifer H Madenspacher; Rhonda H Wilson; Gregory S Whitehead; Hideki Nakano; Arun R Pandiri; Julie F Foley; Alan T Remaley; Donald N Cook; Michael B Fessler Journal: J Immunol Date: 2012-04-25 Impact factor: 5.422
Authors: Wan-Chi Lin; Kymberly M Gowdy; Jennifer H Madenspacher; Rachel L Zemans; Kazuko Yamamoto; Miranda Lyons-Cohen; Hideki Nakano; Kyathanahalli Janardhan; Carmen J Williams; Donald N Cook; Joseph P Mizgerd; Michael B Fessler Journal: J Clin Invest Date: 2020-01-02 Impact factor: 14.808
Authors: Jennifer H Madenspacher; Eric D Morrell; Kymberly M Gowdy; Jeffrey G McDonald; Bonne M Thompson; Ginger Muse; Jennifer Martinez; Seddon Thomas; Carmen Mikacenic; Jerry A Nick; Edward Abraham; Stavros Garantziotis; Renee D Stapleton; Julie M Meacham; Mary Jane Thomassen; William J Janssen; Donald N Cook; Mark M Wurfel; Michael B Fessler Journal: JCI Insight Date: 2020-06-04